Synergistic antibacterial compositions



United States Patent 3,445,398 SYNERGISTIC ANTIBACTERIAL COMPOSITIONS Eric Jungermann, Chicago, and David Taber, Evanston, Ill., assignors to Armour and Company, Chicago, 11]., a corporation of Delaware No Drawing. Filed Apr. 7, 1967, Ser. No. 629,067 Int. Cl. Clld 9/50, 3/48 U.S. Cl. 252107 5 Claims ABSTRACT OF THE DISCLOSURE Compositions possessing antibacterial activity through the use of a synergistic mixture of 3,4,4'-trichlorocarbanilide and 2,4,4'-trichloro-2'-hydroxydiphenyl ether and in which the ratio of carbanilide to the diphenyl ether is from about nine to forty parts of the carbanilide to about one part of the diphenyl ether.

Background of the invention The present invention relates to antibacterial compositions which possess synergistic activity through the use of a mixture of antibacterial agents. More specifically the present invention relates to a mixture of 3,4,4-trichlorocarbanilide and a chlorohydroxyphenyl phenyl ether, 2,4,4 trichloro 2' hydroxydiphenyl ether having the formula:

During the past decade there have been extensive investigations to develop new antibacterial agents, particularly for use in various detergent and cosmetic preparations. It is now estimated that more than 20% of the toilet bar soap sales are products which contain an antibacterial system, and this percentage is steadily increasing. A number of compounds have been suggested for use in antibacterial detergent and cosmetic preparations, and probably the most popular among these is hexachlorophene. Although hexachlorophene is an effective antibacterial agent, and retains its activity even in the presence of a detergent medium such as soap, it does have a tendency to cause discoloration in a detergent product when such product is exposed to light. According to U.S. Patent 3,177,115, hexachlorophene and certain halogenated carbanilides possess synergistic activity, that is the degree of antibacterial activity of the halogenated carbanilides and hexachlorophene in combination is far greater than the antibacterial activity of these. agents when taken independently. The discovery of synergism between hexachlorophene and certain of the halogenated carbanilides was important in that it permitted soap manufacturers and others to provide detergent compositions which have a high level of antibacterial activity, but on the other hand have a greatly reduced concentration of antibacterial agents. The discovery was of further importance because one could then substantially decrease the amount of hexachlorophene employed in the antibacterial composition and thereby greatly reduce the tendency of such compositions to discolor upon prolonged exposure to light.

It has been previously found by others that antibacterial properties are imparted to various compositions by the incorporation therein of chlorohydroxyphenyl phenyl ethers. In British 1,038,185 to J. R. Geigy A.G. it is stated that such chlorohydroxyphenyl phenyl ethers are potent antibacterial agents and are active against gram positive as well as gram negative bacteria. The prepara- 3,445,398 Patented May 20, 1969 Summary of the invention In accordance with this invention it has been found that mixtures of 3,4,4'-trichlorocarbanilide and 2,4,4'-trichloro-2'-hydroxydiphenyl ether exhibit synergistic antibacterial activity and this activity is maintained when such mixtures are incorporated into various detergent compositions such as soap and also in cosmetic preparations.

It is therefore an object of this invention to provide antibacterial compositions which include as antibacterial agents a synergistic combination of 3,4,4'-trichlorocarbanilide and 2,4,4'-trichloro-2'-hydroxydiphenyl ether.

It is still a further object of this invention to provide antibacterial agents which are effective in soap and in other detergent and cosmetic mediums.

It is another object of this invention to provide antibacterial compositions which are effective against both gram positive and gram negative bacteria. Other objects and advantages and a fuller understanding of our invention will become apparent from the ensuing description and examples.

Description of the preferred embodiments In a specific embodiment our invention may be exemplified by a soap composition containing as the active antibacterial ingredient a synergistic mixture of (A) 3,4,4'-trichlorcarbanilide and (B) 2,4,4-trichloro-2'-hydroxydiphenyl ether wherein the ratio of A to B present in the soap is from about nine to forty parts of A to about one part of B.

It is found that when the halogenated carbanilide and the chlorohydroxyphenyl phenyl ether, as set forth above, are used together, a germicidal effect is achieved which is greater than the mere total of the individual effects of the individual ingredients. This has importance in cases where it is desirable to increase the activity of the carbanilide without employing higher concentrations, and in other cases, it assumes an even greater importance from an economic standpoint, since the presence of the chlorohydroxyphenyl phenyl ether enables a reduction in the total concentration of the antibacterial agent While at the same time retaining the desired level of antibacterial effect.

What the actual mechanism of the potentiating or synergistic effect is, we cannot explain. The invention relates to the synergistic cooperation of these two agents when used in minor proportions in various compositions, especially antibacterial detergent compositions such as soap, and the discovery that this synergistic phenomenon occurs even at the high pH conditions existing in soap and other detergent formulations provides one of the important aspects of this invention.

Relatively small amounts of the carbanilide and the chlorohydroxyphenyl phenyl ether are sufficient for the increased antibacterial elfect. Satisfactory results can be obtained when the combined weights of the above two agents are from 0.3% to 2.5% of the total weight of the composition. A preferred range is the weight concentration of about 0.5% to 1.5% and an excellent product is one containing soap and 1% of the carbanilide and about 0.10% of the chlorohydroxyphenyl phenyl ether. It should be understood that even concentrations below the ranges set out above will provide some degree of antibacterial effect and a substantially higher concentration than those referred to will also give satisfactory results, although there are certain practical considerations such as the cost of the two agents which limits the desirability of greater amounts of the germicidal composition in the soap or other medium.

As indicated above, the ratio of the preferred range of the carbanilide to the ehlorohydroxyphenyl phenyl ether is from about 9 to 40 parts of the carbanilide to about 1 part of the chlorohydroxyphenyl phenyl ether, the parts being by weight. In other words, in a soap containing an antibacterial concentration of 3,4,4'-trichlorocarbanilide, the chlorohydroxyphenyl phenyl ether is preferably used in the proportion of 1 part of the chlorohydroxyphenyl phenyl ether to from 9 to 40 parts of the carbanilide.

The term soap refers to the water-soluble ammonium, metallic, or organic base salts of various fatty acids, which are chiefly lauric, oleic, stearic, and palmitic acids. As used in this description, the term is intended to cover all products in which soap is a major constituent, for example, bar, flake, powdered, soft and liquid soaps; shaving creams, toothpaste, cleansing creams, etc.

The anionic type and nonionic type synthetic detergents can be used in place of the soap. The anionic type synthetics suitable for use in the invention can be described as those detergents having pronounced cleansing power and including in their molecular structure an alkyl radical containing from 6 to 18 carbon atoms and a sulfonic acid or sulfuric acid ester radical. Either organic base, ammonium, sodium or potassium salts of the anionic type detergents can be used. The main types of detergents falling within this category are alkyl-aryl sulfonates, such as sodium or potassium dodecyl benzene sulfonate, sodium or potassium octadecyl benzene sulfonate, and sodium or potassium octyl naphthalene sulfonate; the alkyl sulfates, such as sodium or potassium salts of dodecyl, hexadecyl, and octadecyl sulfates; the sulfonated fatty acid amides, such as sodium or potassium salts of the oleic acid amide of methyl taurine; and the sulfonated monoglycerides such as the mono-coconut oil fatty acid ester of sodium 1,2-hydroxypropane-3-sulfonate.

The nonionic type synthetic detergents suitable for use in the invention may be described as those detergents which do not ionize in solution but owe their watersolubility to un-ionized polar groups such as hydroxy or other linkages. The main types of detergents falling within this category are the polyoxyethylene ethers of the higher fatty alcohols and alkyl phenols; the polyethylene glycols of fatty acids; fatty alkylol amide condensation products; polymers of ethylene and propylene oxides; compounds formed by the addition of propylene oxide to ethylene diamine, followed by the addition of ethylene oxide; fatty acid ethylene oxide condensation products; condensation products of ethylene oxide and a fatty acid ester of a polyhydric alcohol or sugar; and the detergents prepared by heating together a higher fatty acid with a diethanolamine. Some examples of synthetic nonionics suitable for the purpose of this invention are ethylene oxide-tall oil fatty acid reaction products; isooctyl phenol-ethylene oxide reaction products; propylene oxide-ethylene oxide reaction products; and combinations of isooctyl phenolethylene oxide with coconut oil fatty acid ethylene oxide reaction products.

The synergistic combinations of the 3,4,4'-trichlorocarbanilide and the 2,4,4'-trichloro-2-hydroxydiphenyl ether can be added to the soap and other detergents by any suitable method which results in a uniform distribution of the agents throughout the entire mass.

Specific examples illustrating the invention are set out as follows:

EXAMPLE I A convenient and meaningful method of measuring the effectiveness of antibacterial compositions is by means of a modified agar streak method utilizing varying amounts and ratios of the individual antibacterial agents in a toilet soap medium. Briefly the test consists of making serial dilutions of soap containing varying amounts and proportions of the antibacterial agents. All solutions are maintained at 60 C. until they are dispensed. Aliquots of the dilutions are dispensed into measured amounts of nutrient agar at 50 C. and thoroughly dispersed. Plates are poured, allowed to solidify and streaked with a standard 4 mm. loopful of a 24-hour broth culture of Staphylococcus aureus FDA 209. After incubation for 24 hours at 37 C., the bacteriostatic end point is determined. The bacteriostatic end point, hereinafter called the minimum inhibitory concentration, represents the minimum concentration in p.p.m. (parts per million) of the bacteriostatic agent or combination of agents necessary to inhibit all growth of the inoculant organism. No particular minimum inhibitory concentration has been established to determine the usefulness of an antibacterial agent, although the lower the end point the better the antibacterial activity and the smaller will be the amount of the agent or agents necessary to maintain a particular degree of effectiveness. The soap utilized for these evaluations was a neutral white toilet soap containing about 20% by weight of sodium coco soap and about by weight of sodium tallow soap.

Using the modified agar streak method as described above, the antibacterial effectiveness of varying amounts and varying ratios of the component active agents" was determined. In this manner a ratio study of the synergistic pair 3,4,4-trichlorocarbanilide and 2,4,4'-trichloro-2- hydroxydiphenyl ether was carried out, the results of which are summarized in the following table.

TABLE Initial concentration of agent in the soap Minimum inhibitory concentration, TCC 1 DPE 2 p.p.m. of agent;

1 3,4,4-trichlorocarbanilide. 2 2,4,4-trichloro-2-hydroxydiphcnyl ether.

As shown above, synergistic results were obtained when the ratio of TCC to DPE was between 9 to 40 parts by weight of TCC to one part by Weight of DPE.

The results hereinabove set out with respect to a specific soap (20% sodium coco and 80% sodium tallow soap) are obtained with soaps generally. Thus, any fatty acid soap such as sodium laurate, potassium stearate, sodium oleate, and potassium myristate will produce these results. The synergistic action is independent of the soap medium and will take place in non-detergent media as Well as in anionic detergents other than soap and in nonionic systems. At the same time, soap is a system in which the synergistic components are highly effective.

While this invention has been described in and exemplified in terms of its preferred embodiments, those skilled in the art will appreciate that variations can be made without departing from the spirit and scope of the invention.

What is claimed is:

1. Antibacterial compositions consisting essentially of a detergent selected from the group consisting of fatty acid water-soluble soaps, anionic and nonionic synthetic organic detergents, and from 0.3% to 2.5% by weight of said detergent of a synergistic combination of 3,4,4-trichlorocarbanilide and 2,4,4 triehloro 2 hydroxydiphenyl ether wherein the ratio of said carbanilide to said diphenyl ether in the detergent is from about nine to forty parts of said carbanilide to about one part of said diphenyl ether, said parts being by weight. 7

2. The antibacterial compositions of claim 1 wherein said detergent is a fatty acid water-soluble soap.

3. Antibacterial compositions according to claim 1 wherein said detergent is a sodium soap of higher fatty acids and wherein the total concentration of said carbanilide and said diphenyl ether is about 1.1% by weight of said detergent.

4. Antibacterial compositions according to claim 1 wherein said detergent is an anionic synthetic organic gent.

5. Antibacterial compositions according to claim 1 wherein said detergent is a nonionic synthetic organic detergent.

6 References Cited UNITED STATES PATENTS 3,177,115 4/1965 Casely et a1. 252107 3,284,362 11/1966 Zussmann.

FOREIGN PATENTS 6,401,526 8/1964 Netherlands.

HERBERT B. GUYNN, Primary Examiner.

10 P. E. WILLIS, Assistant Examiner.

US. Cl. X.R. 252106; 424-324 Notice of Adverse Decision in Interference In Interference No. 98,060, involving Patent No. 3,445,398, E. Jungermenu and D. Taber, SYN ERGISTIC ANTIBACTERIAL COMPOSI- TIONS, final judgment adverse to the patentees was rendered Sept. 30, 1975, as to claims 4 and 5.

[Official Gazette October 25, 1977.] 

